Isoindolinone derivatives

ABSTRACT

The present invention relates to compounds of the formula I, 
                         
as well as pharmaceutically-acceptable salts thereof, pharmaceutical compositions containing said compounds and methods of using said compounds in the treatment or prophylaxis of diseases and disorders. The compounds and compositions disclosed herein are glucokinase activators useful for the treatment or prophylaxis of metabolic diseases and disorders, for example diabetes mellitus, including type II diabetes mellitus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Non-Provisional applicationSer. No. 13/455,169, filed Apr. 25, 2012, which claims the benefit ofU.S. Provisional Application No. 61/481,789, filed May 3, 2011, which ishereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds useful as glucokinaseactivators for the treatment or prophylaxis of metabolic diseases anddisorders.

BACKGROUND OF THE INVENTION

Glucokinase (GK), also referred to as Hexokinase IV, is one of fourhexokinases that are found in mammals. Hexokinases catalyze the firststep in the metabolism of glucose, i.e., the conversion of glucose toglucose-6-phosphate. GK has been found to have a critical role inwhole-body glucose homeostasis. As such, activation of GK represents apotentially important therapeutic intervention point and small moleculeGK activators have considerable potential for the treatment orprophylaxis of metabolic diseases and disorders, for example, Type IIdiabetes.

SUMMARY OF THE INVENTION

The present invention is directed in part to compounds of formula (I),

wherein:R₁ is selected from the group consisting of: H, F, and CF₃;R₂ is selected from the group consisting of: isopropyl, cyclopropyl,cyclopentyl, cyclohexyl, and —CH₂—S—CH₃;R₃ is

R₄ is selected from the group consisting of: H, Br, and —CH(OH)—CH₂OH;andR₅ is selected from the group consisting of: —CH(OH)—CH₂OH,—CH₂—C(CH₃)₂—O—CH₃, —CH₂—CH₂OH, —CH₂—C(O)—O—C(CH₃)₃, —(CH₂)₂O—CH₃,—CH₂—COOH, —(CH₂)₂—COOH, —(CH₂)₂—C(O)—O—C(CH₃)₃, —(CH₂)₂—CH₂OH,—(CH₂)₂—O—CH(CH₃)₂, and —CH₃; and wherein,when R₃ is

R₁ is CF₃; andR₂ is selected from the group consisting of: isopropyl, cyclopentyl, and—CH₂—S—CH₃; and(2) when R₃ is

R₁ is selected from the group consisting of: H, F, and CF₃; andR₂ is selected from the group consisting of: cyclopentyl, cyclohexyl,and cyclopropyl;or a pharmaceutically-acceptable salt thereof.

The compounds are useful as glucokinase activators for the treatment orprophylaxis of metabolic diseases and disorders, for example diabetesmellitus, including type II diabetes mellitus.

The present invention also relates to a process for the preparation of acompound according to formula (I) comprising the reaction of a compoundof formula (VII),

with a compound of formula (VIII),H₂N—R₃  (VIII),wherein R₁, R₂, and R₃ are as previously defined.

The present invention also relates to a compound according to formula(I), or a pharmaceutically-acceptable salt thereof, for use as atherapeutically active substance.

The present invention also relates to a pharmaceutical composition,comprising a compound according to formula (I), or apharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable carrier.

The present invention also relates to the use of a compound according toformula (I), or a pharmaceutically-acceptable salt thereof, for thetreatment or prophylaxis of a metabolic disease or disorder.

The present invention also relates to the use of a compound according toformula (I), or a pharmaceutically-acceptable salt thereof, for thepreparation of a medicament for the treatment or prophylaxis of ametabolic disease or disorder.

The present invention also relates to a compound according to formula(I), or a pharmaceutically-acceptable salt thereof, for the treatment orprophylaxis of a metabolic disease or disorder.

The present invention also relates to a compound according to formula(I), or a pharmaceutically-acceptable salt thereof, prepared accordingto the aforementioned process for preparing said compound.

The present invention also relates to a method for activatingglucokinase comprising administering to a patient atherapeutically-effective amount of a compound according to formula (I),or a pharmaceutically-acceptable salt thereof.

The present invention also relates to a method for the treatment orprophylaxis of a metabolic disease or disorder, which method comprisesadministering to a patient in need thereof a therapeutically-effectiveamount of a compound according to formula (I), or apharmaceutically-acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the terminology employed herein is for thepurpose of describing particular embodiments and is not intended to belimiting. Further, although any methods, devices and materials similaror equivalent to those described herein can be used in the practice ortesting of the invention, the preferred methods, devices and materialsare now described.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety.

The nomenclature used in this Application is based on IUPAC systematicnomenclature, unless indicated otherwise.

Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atomin the structures herein indicates the presence of a hydrogen, unlessindicated otherwise.

The definitions described herein apply irrespective of whether the termsin question appear alone or in combination. It is contemplated that thedefinitions described herein may be appended to form chemically-relevantcombinations, such as e.g. “heterocycloalkyl-aryl”,“haloalkyl-heteroaryl”, “aryl-alkyl-heterocycloalkyl”, or“alkoxy-alkyl”. The last member of the combination is a radical which issubstituted by the other members of the combination in inverse order.

The term “substituted” denotes that a specified group bears one or moresubstituents. Where any group may carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating thenumber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

The term “compound(s) of this invention” and “compound(s) of the presentinvention” refers to compounds of formula I and stereoisomers,tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts)thereof.

It will be appreciated, that the compounds of present invention may bederivatized at functional groups to provide derivatives which arecapable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of present invention invivo are also within the scope of this invention.

The term “prodrug” denotes a form or derivative of a compound which ismetabolized in vivo, e.g., by biological fluids or enzymes by a subjectafter administration, into a pharmacologically active form of thecompound in order to produce the desired pharmacological effect.Prodrugs are described e.g. in “The Organic Chemistry of Drug Design andDrug Action”, by Richard B. Silverman, Academic Press, San Diego, 2004,Chapter 8 Prodrugs and Drug Delivery Systems, pp. 497-558.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts.

The term “pharmaceutically acceptable acid addition salt” denotes thosepharmaceutically acceptable salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and organic acids selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic, and sulfonic classes of organic acids such as formic acid,acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid,succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid,ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamicacid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes thosepharmaceutically acceptable salts formed with an organic or inorganicbase. Examples of acceptable inorganic bases include sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum salts. Salts derived from pharmaceutically acceptable organicnontoxic bases includes salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and polyamine resins.

The term “solvate” denotes crystal forms having either stoichiometric ornonstoichiometric amounts of a solvent incorporated in the crystallattice. If the incorporated solvent is water, the solvate formed is ahydrate. When the incorporated solvent is alcohol, the solvate formed isan alcoholate.

Structures depicted herein are also meant to include compounds thatdiffer only in the presence of one or more isotopically enriched atoms.For example wherein one or more hydrogen atoms are replaced bydeuterium, or one or more carbon atoms are replaced by a 13C- or14C-enriched carbon are within the scope of this invention.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. In describing an optically active compound, the prefixes Dand L, or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The substituents attached to thechiral center under consideration are ranked in accordance with theSequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem.Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and(−) are employed to designate the sign of rotation of plane-polarizedlight by the compound, with (−) or L designating that the compound islevorotatory. A compound prefixed with (+) or D is dextrorotatory.

The term “stereoisomer” denotes a compound that possesses identicalmolecular connectivity and bond multiplicity, but which differs in thearrangement of its atoms in space.

The term “chiral center” denotes a carbon atom bonded to fournonidentical substituents. The term “chiral” denotes the ability ofnon-superimposability with the mirror image, while the term “achiral”refers to embodiments which are superimposable with their mirror image.Chiral molecules are optically active, i.e., they have the ability torotate the plane of plane-polarized light.

Compounds of present invention can have one or more chiral centers andcan exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. Whenever a chiralcenter is present in a chemical structure, it is intended that allstereoisomers associated with that chiral center are encompassed by thepresent invention.

The term “enantiomers” denotes two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “diastereomer” denotes a stereoisomer with two or more centersof chirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities.

The term “racemate” or “racemic mixture” refers to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms, in particular of 1 to 7carbon atoms, more particular of 1 to 4 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, ortert-butyl.

The term “active pharmaceutical ingredient” (or “API”) denotes thecompound in a pharmaceutical composition that has a particularbiological activity.

The term “pharmaceutically-acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use.

The term “pharmaceutically-acceptable excipient” denotes any ingredienthaving no therapeutic activity and being non-toxic such asdisintegrators, binders, fillers, solvents, buffers, tonicity agents,stabilizers, antioxidants, surfactants or lubricants used in formulatingpharmaceutical products.

The term “pharmaceutical composition” (or “composition”) denotes amixture or solution comprising a therapeutically effective amount of anactive pharmaceutical ingredient together with pharmaceuticallyacceptable-excipients to be administered to a mammal, e.g., a human inneed thereof.

The term “lyophilization” and variations thereof (e.g., “lyophilized”)refers to the process of freezing a substance and then reducing theconcentration of water, by sublimation and/or evaporation to levelswhich do not support biological or chemical reactions.

The term “reconstituted composition” in connection with the compositionaccording to the invention denotes a lyophilized composition which isre-dissolved by addition of reconstitution medium. The reconstitutionmedium comprises water for injection (WFI), bacteriostatic water forinjection (BWFI), sodium chloride solutions (e.g. 0.9% (w/v) NaCl),glucose solutions (e.g. 5% glucose), surfactant comprising solutions(e.g. 0.01% polysorbate 20), or pH-buffered solution (e.g.phosphate-buffered solutions).

The term “sterile” denotes that a composition or excipient has aprobability of being microbially contaminated of less than 10⁻⁶.

The term “buffer” denotes a pharmaceutically acceptable excipient, whichstabilizes the pH of a pharmaceutical preparation. Suitable buffers arewell known in the art and can be found in the literature. Particularpharmaceutically acceptable buffers comprise histidine-buffers,arginine-buffers, citrate-buffers, succinate-buffers, acetate-buffersand phosphate-buffers. Independently from the buffer used, the pH can beadjusted with an acid or a base known in the art, e.g. hydrochloricacid, acetic acid, phosphoric acid, sulfuric acid and citric acid,sodium hydroxide and potassium hydroxide.

The term “tonicity” denotes a measure of the osmotic pressure of twosolutions separated by a semi-permeable membrane. Osmotic pressure isthe pressure that must be applied to a solution to prevent the inwardflow of water across a semi-permeable membrane. Osmotic pressure andtonicity are influenced only by solutes that cannot cross the membrane,as only these exert an osmotic pressure. Solutes able to freely crossthe membrane do not affect tonicity because they will always be in equalconcentrations on both sides of the membrane.

Tonicity in general relates to the osmotic pressure of a solutionusually relative to that of human blood serum. A composition can behypotonic, isotonic or hypertonic. An isotonic composition is liquid orliquid reconstituted from a solid form, e.g. from a lyophilized form,and denotes a solution having the same tonicity as some other solutionwith which it is compared, such as physiologic salt solution and theblood serum.

The term “surfactant” denotes a pharmaceutically acceptable excipientwhich is used to protect protein compositions against mechanicalstresses like agitation and shearing. Examples of pharmaceuticallyacceptable surfactants include poloxamers, polysorbates, polyoxyethylenealkyl ethers (Brij), alkylphenylpolyoxyethylene ethers (Triton-X) orsodium dodecyl sulfate (SDS).

The term “poloxamer” denotes non-ionic triblock copolymers composed of acentral hydrophobic chain of polypropylene oxide) (PPO) flanked by twohydrophilic chains of poly(ethylene oxide) (PEO), each PPO or PEO chaincan be of different molecular weights. Poloxamers are also known by thetrade name Pluronics. Particular Poloxamer is Poloxamer 188, a poloxamerwherein the PPO chain has a molecular mass of 1800 g/mol and a PEOcontent of 80% (w/w).

The term “polysorbate” denotes oleate esters of sorbitol and itsanhydrides, typically copolymerized with ethylene oxide. Particularpolysorbates are Polysorbate 20 (poly(ethylene oxide) (20) sorbitanmonolaurate, Tween 20) or Polysorbate 80 (poly(ethylene oxide) (80)sorbitan monolaurate, Tween 80).

The term “antioxidant” denotes pharmaceutically acceptable excipients,which prevent oxidation of the active pharmaceutical ingredient.Antioxidants comprise ascorbic acid, glutathione, cysteine, methionine,citric acid, EDTA.

The term “tonicity agent” denotes pharmaceutically acceptable excipientused to modulate the tonicity of a composition. Suitable tonicity agentscomprise amino acids and sugars. Particular tonicity agents aretrehalose, sucrose or arginine.

The term “sugar” denotes a monosaccharide or an oligosaccharide. Amonosaccharide is a monomeric carbohydrate which is not hydrolysable byacids, including simple sugars and their derivatives, e.g. aminosugars.Examples of monosaccharides include glucose, fructose, galactose,mannose, sorbose, ribose, deoxyribose, neuraminic acid. Anoligosaccharide is a carbohydrate consisting of more than one monomericsaccharide unit connected via glycosidic bond(s) either branched or in achain. The monomeric saccharide units within an oligosaccharide can beidentical or different. Depending on the number of monomeric saccharideunits the oligosaccharide is a di-, tri-, tetra- penta- and so forthsaccharide. In contrast to polysaccharides the monosaccharides andoligosaccharides are water soluble. Examples of oligosaccharides includesucrose, trehalose, lactose, maltose and raffinose.

The term “treating” or “treatment” of a disease state includes (1)preventing the disease state, i.e. causing the clinical symptoms of thedisease state not to develop in a subject that may be exposed to orpredisposed to the disease state, but does not yet experience or displaysymptoms of the disease state, (2) inhibiting the disease state, i.e.,arresting the development of the disease state or its clinical symptoms,or (3) relieving the disease state, i.e., causing temporary or permanentregression of the disease state or its clinical symptoms.

The term “therapeutically effective amount” denotes an amount of acompound of the present invention that, when administered to a subject,(i) treats or prevents the particular disease, condition or disorder,(ii) attenuates, ameliorates or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, conditionor disorder described herein. The therapeutically effective amount willvary depending on the compound, disease state being treated, theseverity of the disease treated, the age and relative health of thesubject, the route and form of administration, the judgment of theattending medical or veterinary practitioner, and other factors.

The term “subject” denotes a vertebrate. In certain embodiments, thevertebrate is a mammal. Mammals include humans, non-human primates suchas chimpanzees and other apes and monkey species, farm animals such ascattle, horses, sheep, goats, and swine, domestic animals such asrabbits, dogs, and cats, laboratory animals including rodents, such asrats, mice, and guinea pigs. In certain embodiments, a mammal is ahuman. The term subject does not denote a particular age or sex.

In an embodiment of the present invention, provided are compound offormula (I):

wherein:R₁ is selected from the group consisting of: H, F, and CF₃;R₂ is selected from the group consisting of: isopropyl, cyclopropyl,cyclopentyl, cyclohexyl, and —CH₂—S—CH₃;R₃ is

R₄ is selected from the group consisting of: H, Br, and —CH(OH)—CH₂OH;andR₅ is selected from the group consisting of: —CH(OH)—CH₂OH,—CH₂—C(CH₃)₂—O—CH₃, —CH₂—CH₂OH, —CH₂—C(O)—O—C(CH₃)₃, —(CH₂)₂O—CH₃,—CH₂—COOH, —(CH₂)₂—COOH, —(CH₂)₂—C(O)—O—(CH₃)₃, —(CH₂)₂—CH₂OH,—(CH₂)₂—O—CH(CH₃)₂, and —CH₃;and wherein,when R₃ is

R₁ is CF₃; andR₂ is selected from the group consisting of: isopropyl, cyclopentyl, and—CH₂—S—CH₃; and(2) when R₃ is

R₁ is selected from the group consisting of: H, F, and CF₃; andR₂ is selected from the group consisting of: cyclopentyl, cyclohexyl,and cyclopropyl;or a pharmaceutically-acceptable salt of said compound.

Compounds of formula (I) can have one or more asymmetric carbon atomsand can exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbents or eluant). The invention embraces all of theseforms.

In the compound of formula I, the asterisk denotes an asymmetric carbonatom. The compound of formula I may be present as a racemate or ineither the R or S configurations. In a particular embodiment of thepresent invention, the compound is in the S configuration.

In an embodiment, the compound is a compound of formula (I), wherein

R₃ is

In an embodiment, the compound is a compound of formula (I) selectedfrom the group consisting of:

-   (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide;-   (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)—N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide;-   (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic    acid pyrazin-2-ylamide;-   (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic    acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide;    and pharmaceutically-acceptable salts thereof.

In an embodiment, the compound is a compound of formula (I), wherein R₃is

In an embodiment, the compound is a compound of formula (I) selectedfrom the group consisting of:

-   (S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid tert-butyl ester;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid;-   (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopropyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid tert-butyl ester;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid;    and pharmaceutically-acceptable salts thereof.

In an embodiment, the compound is a compound of formula (I), wherein R₁is CF₃.

In an embodiment, the compound is a compound of formula (I), selectedfrom the group consisting of:

-   (S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid tert-butyl ester;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid;-   (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide;-   (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid tert-butyl ester;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid;-   (S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)—N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide;-   (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic    acid pyrazin-2-ylamide;-   (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic    acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide;    and pharmaceutically-acceptable salts thereof.

In an embodiment, the compound is a compound of formula (I), wherein R₂is cyclopentyl.

In an embodiment, the compound is a compound of formula (I), selectedfrom the group consisting of:

-   (S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid tert-butyl ester;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid;-   (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide;-   (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid tert-butyl ester;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid;-   (S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;    and pharmaceutically-acceptable salts thereof.

In an embodiment, the compound is a compound of formula (I), wherein R₁is H.

In an embodiment, the compound is a compound of formula (I), selectedfrom the group consisting of:

-   (S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopropyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide;    and pharmaceutically-acceptable salts thereof.

In an embodiment, the compound is a compound of formula (I), wherein R₁is CF₃, R₂ is cyclopentyl, and R₃ is

In an embodiment, the compound is a compound of formula (I) selectedfrom the group consisting of:

-   (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide;-   (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;    and pharmaceutically-acceptable salts thereof.

In an embodiment, the compound is a compound of formula (I), wherein R₁is CF₃, R₂ is cyclopentyl, and R₃ is

In an embodiment, the compound is a compound of formula (I) selectedfrom the group consisting of:

-   (S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid tert-butyl ester;-   {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic    acid;-   (S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   (S)-3-cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid tert-butyl ester;-   3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic    acid;    and pharmaceutically-acceptable salts thereof.

In an embodiment of the present invention, there is provided a compoundaccording to formula (I), or a pharmaceutically acceptable-salt thereof,for use as a therapeutically active substance, for example, for thetreatment of a metabolic disease or disorder.

In another embodiment of the present invention, there is provided theuse of a compound according to formula (I), or apharmaceutically-acceptable salt thereof, for the treatment orprophylaxis of a metabolic disease or disorder.

The invention further provides the use of a compound according toformula (I), or a pharmaceutically-acceptable salt thereof, for thepreparation of a medicament for the treatment or prophylaxis of ametabolic disease or disorder.

The invention further provides a compound according to formula (I), or apharmaceutically-acceptable salt thereof, for the treatment orprophylaxis of a metabolic disease or disorder.

The present invention also relates to a method for the treatment orprophylaxis of a metabolic disease or disorder, which method comprisesadministering to a patient in need thereof a therapeutically-effectiveamount of a compound according to formula (I), or apharmaceutically-acceptable salt thereof.

In an embodiment of the present invention, the compound according toformula (I), or a pharmaceutically-acceptable salt thereof, isadministered at a dose that is within the range of from about 1 to about1000 mg per day, in particular from about 1 mg to about 500 mg per day.

In the practice of the method of the present invention, a compoundaccording to formula (I), or a pharmaceutically-acceptable salt thereof,is administered via any of the usual and acceptable methods known in theart, either singly or in combination. The compounds or compositions canthus be administered orally (e.g., buccal cavity), sublingually,parenterally (e.g., intramuscularly, intravenously, or subcutaneously),rectally (e.g., by suppositories or washings), transdermally (e.g., skinelectroporation) or by inhalation (e.g., by aerosol), and in the form orsolid, liquid or gaseous dosages, including tablets and suspensions. Theadministration can be conducted in a single unit dosage form withcontinuous therapy or in a single dose therapy ad libitum. Thepharmaceutical composition can also be in the form of an oil emulsion ordispersion in conjunction with a lipophilic salt such as pamoic acid, orin the form of a biodegradable sustained-release composition forsubcutaneous or intramuscular administration.

The present invention provides a pharmaceutical composition, comprisingof a compound according to formula (I), or a pharmaceutically-acceptablesalt thereof, and a pharmaceutically-acceptable carrier.

Useful pharmaceutically-acceptable carriers for the preparation of thecompositions hereof, can be solids, liquids or gases. Thus, thecompositions can take the form of tablets, pills, capsules,suppositories, powders, enterically coated or other protectedformulations (e.g. binding on ion-exchange resins or packaging inlipid-protein vesicles), sustained release formulations, solutions,suspensions, elixirs, aerosols, and the like. The carrier can beselected from the various oils including those of petroleum, animal,vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineraloil, sesame oil, and the like. Water, saline, aqueous dextrose, andglycols are preferred liquid carriers, particularly (when isotonic withthe blood) for injectable solutions. For example, formulations forintravenous administration comprise sterile aqueous solutions of theactive ingredient(s) which are prepared by dissolving solid activeingredient(s) in water to produce an aqueous solution, and rendering thesolution sterile. Suitable pharmaceutically-acceptable excipientsinclude starch, cellulose, talc, glucose, lactose, talc, gelatin, malt,rice, flour, chalk, silica, magnesium stearate, sodium stearate,glycerol monostearate, sodium chloride, dried skim milk, glycerol,propylene glycol, water, ethanol, and the like. The compositions may besubjected to conventional pharmaceutical additives such aspreservatives, stabilizing agents, wetting or emulsifying agents, saltsfor adjusting osmotic pressure, buffers and the like. Suitablepharmaceutical carriers and their formulation are described inRemington's Pharmaceutical Sciences by E. W. Martin. Such compositionswill, in any event, contain a therapeutically-effective amount of thecompound according to formula (I), or a pharmaceutically-acceptable saltthereof and a pharmaceutically-acceptable carrier so as to prepare theproper dosage form for proper administration to the recipient.

Compounds of formula I can be prepared as outlined in the general schemebelow. Compounds of formula II (where R₁ is F or CF₃) may be treatedwith hydrochloric acid in methanol at reflux to produce compounds offormula III. Compounds of formula III may then be treated withN-bromosuccinimide in carbon tetrachloride with catalytic benzoylperoxide, at 80° C., to produce compounds of formula IV. Compounds offormula IV may then be treated with compounds of formula V andtriethylamine in acetonitrile in a microwave reactor at 110° C. toproduce a compound of formula VI. Alternatively, compounds of formula IVmay be treated with ammonia in methanol to produce compounds of formulaIX. Compounds of formula IX may be treated sodium hydride intetrahydrofuran, followed by a compound of formula X, to produce acompound of formula VI. Compounds of formula VI may be saponified usinglithium hydroxide in water/tetrahydrofuran to produce a compound offormula VII (where R₁=F or CF₃). Alternatively, compounds of formula VII(where R₁=H) can be prepared by treating phthalic dicarboxaldehyde (XI)with a compound of formula XII. The compound of formula VII may betreated with oxalyl chloride in dichloromethane with a catalytic amountof dimethylformamide followed by a compound of formula VIII indichloromethane with 2,6-lutidine at room temperature to produce acompounds of formula I. Alternatively, compounds of formula VII may betreated with benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate and N,N-diisopropylethylamine along with compoundsof formula VIII in dichloromethane to produce a compounds of formula I.

Compounds of the present invention can be prepared beginning withcommercially available starting materials and utilizing generalsynthetic techniques and procedures known to those skilled in the art.

Compounds of formula II (2-fluoro-3-trifluoromethyl-benzoic acid and2-methyl-3-trifluoromethyl-benzoic acid) are commercially available(Oakwood, Alfa, Apollo). Compounds of formula (V) are commerciallyavailable (Aldrich, Sigma, Alfa, Bachem, Chemimpex) or can be preparedfrom the corresponding amino acid or protected amino acid derivativesusing standard conditions. Amino acids (XII) can be purchased (Aldrich,Sigma, Alfa, Bachem, Chemimpex) or prepared using any number of standardmethods. Compounds of formula X are commercially available (Aldrich,Pfaltz & Bauer, ArkPharm) or can be prepared by brominating thecorresponding methyl ester using standard conditions. The correspondingmethyl esters are commercially available (Aldrich, Pfaltz & Bauer,ArkPharm), or can be prepared from the corresponding acids usingstandard conditions. Phthalic dicarboxaldehyde (XI) is commercially(Sigma Aldrich). Compounds of formula VIII are commercially available(Matrix, Alfa, Oakwood) or can be prepared as described in US20080021032 or WO2004052869.

In an embodiment of the present invention, there is provided a processfor the preparation of a compound of formula (I) or apharmaceutically-acceptable salt thereof comprising the reaction of acompound of formula (VII), as described above, with a compound offormula (VIII), as described above. R₁, R₂, and R₃ are as previouslydefined.

An embodiment of the present invention is a process for the preparationof a compound according to formula (I) comprising the reaction of acompound of formula (VII),

with a compound of formula (VIII), H₂N—R₃,wherein R₁, R₂, and R₃ are as previously defined.

In addition, the invention provides a compound of formula (I), or apharmaceutically-acceptable salt thereof, manufactured according to theabove process.

EXAMPLES

This invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

Chemistry.

All nonaqueous reactions were carried out under an argon or nitrogenatmosphere at room temperature, unless otherwise noted. All reagents andanhydrous solvents were used as obtained commercially without furtherpurification or distillation, unless otherwise stated. Analyticalthin-layer chromatography (TLC) was performed on EMD Chemicals silicagel 60 F254 precoated plates (0.25 mm). Compounds were visualized by UVlight and/or stained with either p-anisaldehyde, iodine, orphosphomolybdic acid or KMnO₄ solutions followed by heating. Analyticalhigh performance liquid chromatography (HPLC) and LC-MS analyses wereconducted using the following two instruments and conditions. Method 1:Hewlett-Packard HP-1090 pump and HP-1090 PDA detector set at 215 nm withthe MS detection performed with a Micromass Platform II massspectrometer with electrospray ionization (ESI); Chromegabond WR C18 3μm, 120 Å, 3.2×30 mm column; solvent A, H₂O-0.02% TFA; solvent B,MeCN-0.02% TFA; flow rate: 2 mL/min; start 2% B, final 98% B in 4 min,linear gradient. Method 2: Waters 2795 pump and Waters 2996 photodiodearray detector set at 214 nm with the MS detection performed with aWaters ZQ mass spectrometer (ESI); Epic Polar Hydrophilic 3 μm, 120 Å,3.2×30 mm column; solvent A, H₂O-0.03% HCO₂H; solvent B, MeCN-0.03%HCO₂H; flow rate) 2 mL/min; start 10% B, final 100% B in 3 min lineargradient, remaining for 1 min. Unless otherwise noted, compounds werepurified using either of the following methods. Flash columnchromatography was performed on EM Science silica gel 60 (particle sizeof 32-63 μm, 60 Å) or commercially available silica gel columncartridges from Biotage, ISCO or Analogix. Preparative reverse-phasehigh-pressure liquid chromatography (RP HPLC) was performed using one ofthe following systems: (A) a Waters Delta prep 4000 pump/controller, a486 detector set at 215 nm, and a LKB Ultrorac fraction collector; or(B) a Sciex LC/MS system with a 150 EX single quad mass spec, a ShimadzuLC system, a LEAP autoinjector, and a Gilson fraction collector. Thesample was dissolved in a mixture of acetonitrile/20 mM aqueous ammoniumacetate or acetonitrile/water/TFA, applied on a Pursuit C-18 20×100 mmcolumn and eluted at 20 ml/min with a linear gradient of 10%-90% B,where (A): 20 mM aqueous ammonium acetate (pH 7.0) and (B): acetonitrileor (A): water with 0.05% TFA and (B): acetonitrile with 0.05% TFA. Thepooled fractions were concentrated under reduced pressure andlyophilized to afford the desired compounds. ¹H NMR spectra wererecorded using a Varian Mercury 300 MHz or Varian Inova 400 MHzspectrometer. All peak listings for the NMR data were generated usingACD Labs 1D NMR Processor version 12.0. The chemical shifts are in partsper million (δ) referenced to DMSO-d5 (2.49 ppm) or CHCl₃ (7.26 ppm).High-resolution mass spectra (HRMS) were recorded on a Bruker Apex IIFTICR mass spectrometers with a 4.7 T magnet (ES) or Micromass AutoSpec(EI) mass spectrometers. Optical rotations were measured on a Schmidt &Haensch electronic polarimeter. The wavelength was set at 589.45 nmwhich is the sodium D line. Temperature was ambient room temperature.Final compounds and intermediates were named using the Auto Nom2000feature in the MDL ISIS Draw application.

Example 1(S)-3-Cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

To a solution of 2-methyl-3-trifluoromethyl-benzoic acid (Apollo, 1 g,4.90 mmol) in methanol (20 mL) was added concentrated sulfuric acid (0.5mL) and the resulting mixture was heated to reflux overnight. The cooledreaction mixture was concentrated and diluted with water (25 mL) and asaturated sodium bicarbonate solution (25 mL). The mixture was extractedwith ethyl acetate (50 mL), the organic phases combined, washed withwater and dried over magnesium sulfate. The mixture was filtered andevaporated to give 2-methyl-3-trifluoromethyl-benzoic acid methyl ester(0.95 g, 4.35 mmol, 89%); ¹H NMR (300 MHz, CDCl₃) δ ppm 2.65 (s, 3H),3.94 (s, 3H), 7.35 (t, J=7.85 Hz, 1H), 7.72-8.01 (m, 2H).

To a solution of 2-methyl-3-trifluoromethyl-benzoic acid methyl ester(0.95 g, 4.35 mmol) in benzene (10 mL) was added N-bromosuccinimide(0.77 g, 4.33 g) and benzoyl peroxide (0.052 g, 0.21 mmol) and theresulting mixture heated to reflux for 4 h, cooled and stirred at roomtemperature for 48 h. The mixture was filtered, the filter cake washedwith diethyl ether and the filtrate washed with a 1 N sodium thiosulfatesolution (10 mL), brine and dried over magnesium sulfate. The mixturewas filtered and evaporated and the residue purified via automated flashchromatography (Analogix, SF25-80 g column, 5→10% ethyl acetate/hexanegradient) to give 2-bromomethyl-3-trifluoromethyl-benzoic acid methylester (1.04 g, 3.50 mmol, 81%) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.72-4.16 (m, 3H), 5.03 (s, 2H), 7.47-8.32 (m, 3H).

(S)-2-Amino-3-cyclopentyl-propionic acid (Chemimpex, 1.0 g, 6.36 mmol),methanol (15 mL) and concentrated hydrochloric acid (2 mL) was placed ina reaction flask and heated at 65° C. for 16 h. After such time, thereaction mixture was concentrated in vacuo and then dissolved in water.The resulting solution was then treated with a saturated aqueous sodiumbicarbonate solution until pH ˜7-9. It was then extracted with ethylacetate and the organic layers combined, dried over magnesium sulfate,filtered to remove the drying agent and the filtrate concentrated invacuo to afford (S)-2-amino-3-cyclopentyl-propionic acid methyl ester(796 mg, 73%) as a clear colorless oil: HR-ES(+) m/e calcd for C₉H₁₇NO₂[M+H]⁺ 172.1332, observed 172.1332; ¹H NMR (300 MHz, DMSO-d6) δ ppm 3.60(s, 3H), 3.25 (dd, J=6.04, 7.85 Hz, 1H), 1.34-1.96 (m, 9H), 0.92-1.14(m, 2H).

A mixture of 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester(695 mg, 2.34 mmol), (S)-2-amino-3-cyclopentyl-propionic acid methylester (400 mg, 2.34 mmol), triethylamine (358 μL, 2.57 mmol), andacetonitrile (20 mL) was heated at 82° C. for 7 h. The crude reactionmixture was treated with water (5 mL) and then concentrated in vacuo toremove the acetonitrile. The remaining solution was then diluted withwater (10 mL) and extracted with ethyl acetate (3×20 mL), the combinedorganics were then dried over magnesium sulfate, filtered to remove thedrying agent and the filtrate concentrated in vacuo. The residue wasthen purified via automated flash chromatography (12 g silica gelcolumn, 10-40% ethyl acetate/hexanes) to afford(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid methyl ester (675 mg, 81%) as a clear colorless oil: [α]²⁵_(D)=−16.0°, (c=0.15, methylene chloride); HR-ES(+) m/e calcd forC₁₈H₂₀NO₃F₃ [M+H]⁺ 356.1468, observed 356.1466; ¹H NMR (300 MHz,DMSO-d6, ppm) δ 8.02 (t, J=8.00 Hz, 2H), 7.71-7.89 (m, 1H), 4.92 (dd,J=4.08, 10.41 Hz, 1H), 4.69 (s, 2H), 3.66 (s, 3H), 0.94-2.21 (m, 11H).

A solution(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid methyl ester (350 mg, 0.98 mmol) in tetrahydrofuran (5 mL) at roomtemperature was treated with a solution of lithium hydroxide monohydrate(82 mg, 1.96 mmol) in water (5 mL). The reaction mixture was thenstirred at room temperature for 1 h. The reaction mixture was thenacidified to pH=2 with a 1 N aqueous hydrochloric acid solution andextracted with ethyl acetate (3×20 mL). The combined organic layers werethen dried over magnesium sulfate, filtered to remove the drying agent,and the filtrate concentrated in vacuo to afford(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (293 mg, 88%) as a colorless oil: [α]²⁸ _(D)=−5.3° (c=0.19,methylene chloride); HR-ES(+) m/e calcd for C₁₇H₁₈NO₃F₃ [M+H]⁺ 342.1312,observed 342.1310; ¹H NMR (300 MHz, DMSO-d6) δ ppm 13.13 (br. s., 1H),8.02 (t, J=8.15 Hz, 2H), 7.68-7.85 (m, 1H), 4.82 (dd, J=4.23, 11.17 Hz,1H), 4.69 (s, 2H), 1.02-2.20 (m, 11H).

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (100 mg, 0.29 mmol) in methylene chloride (2.9 mL) at 0° C. wastreated with oxalyl chloride (0.03 mL, 0.34 mmol) followed byN,N-dimethylformamide (5 drops). The resulting solution was stirred at0° C. for 30 min. At this time, the solution was warmed to roomtemperature and stirred for 30 min. The reaction was then concentratedin vacuo. The residue was re-suspended in methylene chloride (2×5 mL)and then concentrated in vacuo. The residue was then dissolved inmethylene chloride (1 mL) and was added to a pre-cooled solution of1-methyl-1H-pyrazol-3-ylamine (Matrix, 30 mg, 1.05 mmol) and2,6-lutidine (0.05 mL, 0.47 mmol) in methylene chloride (3 mL) at 0° C.The reaction was allowed to gradually warm to room temperature and wasstirred at room temperature overnight. After this time, the reaction wasdiluted with methylene chloride (50 mL) and was washed with a 1N aqueoushydrochloric acid solution (2×100 mL), a saturated aqueous sodiumbicarbonate solution (2×100 mL) and water (1×100 mL), dried over sodiumsulfate, filtered and concentrated in vacuo. Flash chromatography(50-75% ethyl acetate/hexanes) afforded(S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(94 mg, 77%) as a white solid; ES⁺-HRMS m/e calcd for C₂₁H₂₃N₄O₂F₃(M+H)⁺ 421.1846 found 421.1844. ¹H-NMR (300 MHz, DMSO-d₆) δ ppm 10.87(s, 1H), 8.01 (t, J=8.6 Hz, 2H), 7.68-7.81 (m, 1H), 7.54 (d, J=1.9 Hz,1H), 6.39 (d, J=1.9 Hz, 1H), 5.02-5.15 (m, 1H), 5.03 (d, J=18.5 Hz, 1H),4.71 (d, J=18.5 Hz, 1H), 3.73 (s, 3H), 0.98-2.12 (m, 11H).

Example 2(S)-3-Cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole(prepared as in US 20080021032 Example 67, 6.34 g, 23.36 mmol) inethanol (100 mL) was treated with concentrated hydrochloric acid (12drops) and stirred for 1 h at room temperature. After this time, anotherportion of concentrated hydrochloric acid was added (12 drops) and itwas stirred overnight at room temperature. After this time, the reactionmixture was concentrated in vacuo and then azeotroped with acetonitrile.The crude material was then purified by flash column chromatography(silica gel 60, 230-400 mesh, 80% ethyl acetate/hexanes) to afford2-(3-nitro-pyrazol-1-yl)-ethanol (2.36 g, 94%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ ppm 8.00 (d, J=2.56 Hz, 1H), 7.03 (d, J=2.56 Hz,1H), 5.00 (t, J=5.31 Hz, 1H), 4.26 (t, J=5.31 Hz, 2H), 3.77 (q, J=5.49Hz, 2H).

A solution 2-(3-nitro-pyrazol-1-yl)-ethanol (3.46 g, 22.02 mmol) inethanol (40 mL) was placed in a Parr shaker bottle and treated with 10%palladium on carbon (350 mg). The bottle was then put on the Parr shakerand charged with hydrogen to 50 psi and let shake for 1 h. After thistime, the reaction mixture was filtered through celite and the celitewashed with ethanol. The filtrate was then concentrated in vacuo andazeotroped with acetonitrile and then chloroform to afford2-(3-amino-pyrazol-1-yl)-ethanol (3.02 g, >quant.) as a light yellowviscous oil: ¹H NMR (300 MHz, DMSO-d₆ δ ppm 7.26 (d, J=1.83 Hz, 1H),5.34 (d, J=2.20 Hz, 1H), 4.76 (t, J=5.31 Hz, 1H), 4.50 (s, 2H),3.78-3.88 (m, 2H), 3.62 (q, J=5.74 Hz, 2H).

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (50 mg, 0.15 mmol, prepared as in Example 1) in methylene chloride(5 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treatedwith a solution of oxalyl chloride in methylene chloride (2.0 M, 88 μL,0.18 mmol) and stirred at 0° C. for 10 min. After this time, thereaction mixture was warmed to room temperature and then stirred foranother 25 min. After this time, the reaction mixture was thenconcentrated in vacuo and the residue taken up in methylene chloride (2mL) and added dropwise to a separate reaction flask containing a mixtureof 2-(3-amino-pyrazol-1-yl)-ethanol (28 mg, 0.22 mmol) and 2,6-lutidine(32 μL, 0.29 mmol) in methylene chloride (5 mL) cooled to 0° C. Theresulting reaction mixture was then allowed to warm to room temperatureand stirred for 16 h. After such time, the reaction mixture was quenchedwith a saturated aqueous sodium bicarbonate solution (10 mL) and thenextracted with methylene chloride (3×15 mL). The organic layers werethen washed with a 1N aqueous hydrochloric acid solution (10 mL), driedover magnesium sulfate, filtered to remove the drying agent, and thefiltrate concentrated in vacuo. The crude material was purified viaautomated flash chromatography (4 g silica gel column, 60-95% ethylacetate/hexanes) to afford(S)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(57 mg, 86%) as a white foam: [α]²⁹ _(D)=−28.5°, (c=0.26, methylenechloride); HR-ES(+) m/e calcd for C₂₂H₂₅N₄O₃F₃ [M+H]⁺ 451.1952, observed451.1950; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.91 (s, 1H), 8.01 (t, J=8.50Hz, 2H), 7.69-7.81 (m, 1H), 7.56 (d, J=2.27 Hz, 1H), 6.40 (d, J=2.27 Hz,1H), 4.97-5.13 (m, 2H), 4.85 (t, J=5.29 Hz, 1H), 4.71 (d, J=18.51 Hz,1H), 4.02 (t, J=5.67 Hz, 2H), 3.69 (q, J=5.67 Hz, 2H), 0.99-2.12 (m,11H).

Example 3{3-[(S)-3-Cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-aceticacid tert-butyl ester

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride(4 mL) and N,N-dimethylformamide (4 drops) was treated with a solutionof oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) andstirred for 15 min at room temperature. After this time, the reactionmixture was then concentrated in vacuo and the resulting residue wasdissolved in methylene chloride (4 mL) and then added dropwise to aseparate reaction flask containing a mixture of(3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (prepared as in US20080021032, Example 3, 86 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87mmol) in methylene chloride (3 mL) at room temperature. The resultingreaction mixture was then stirred at room temperature for 2 h. Thereaction mixture was then quenched by the addition of methanol and thendiluted with methylene chloride. The organic layer was then concentratedin vacuo with silica gel (2.0 g). The silica gel with absorbed materialwas placed in a SIM and purified via Biotage flash column chromatography(40 S silica gel column, 25% ethyl acetate/hexanes) to afford{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-aceticacid tert-butyl ester (151 mg, 100%) as a white foam: HR-ES(+) m/e calcdfor C₂₆H₃₁N₄O₄F₃ [M+H]⁺ 521.2370, observed 521.2368; ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.49 (s, 1H), 8.08 (d, J=7.46 Hz, 1H), 7.81 (d,J=7.67 Hz, 1H), 7.63 (t, J=7.67 Hz, 1H), 7.33 (d, J=2.34 Hz, 1H), 6.73(d, J=2.34 Hz, 1H), 5.02 (dd, J=7.03, 8.52 Hz, 1H), 4.70-4.81 (m, 1H),4.53-4.69 (m, 3H), 1.10-2.25 (m, 20H).

Example 4{3-[(S)-3-Cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-aceticacid

A mixture of{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-aceticacid tert-butyl ester (133 mg, 0.26 mmol, prepared as in Example 3) andlithium hydroxide monohydrate (22 mg, 0.52 mmol) intetrahydrofuran:water (1:1, 10 mL) at room temperature was stirred for 2h. The reaction mixture was then concentrated in vacuo and partitionedbetween a 1 N aqueous hydrochloric acid solution and ethyl acetate. Theorganic layer was then dried over magnesium sulfate, filtered to removethe drying agent, and the filtrate concentrated in vacuo to afford{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-aceticacid (118 mg, 98%) as a white foam: HR-ES(+) m/e calcd for C₂₂H₂₃N₄O₄F₃[M+H]⁺ 465.1744, observed 465.1744; ¹H NMR (400 MHz, DMSO-d6) δ ppm10.93 (s, 1H), 8.01 (dd, J=7.67, 13.00 Hz, 2H), 7.69-7.80 (m, 1H), 7.59(d, J=2.13 Hz, 1H), 6.45 (d, J=2.13 Hz, 1H), 4.95-5.12 (m, 2H), 4.81 (s,2H), 4.72 (d, J=17.90 Hz, 1H), 1.09-2.11 (m, 11H).

Example 5(S)-3-Cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride(5 mL) and N,N-dimethylformamide (5 drops) was treated with a solutionof oxalyl chloride in methylene chloride (2.0 M, 200 μL, 0.40 mmol) andstirred for 15 min at room temperature. After this time, the reactionmixture was then concentrated in vacuo and the resulting residue wasdissolved in methylene chloride (5 mL) and then added dropwise to aseparate reaction flask containing a mixture of(R)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (prepared as in US20080021032, Example 35, 70 mg, 0.45 mmol) and 2,6-lutidine (250 μL) inmethylene chloride (3 mL) at room temperature. The resulting reactionmixture was then stirred room temperature for 2 h. The reaction mixturewas quenched by the addition of methanol and then diluted with methylenechloride. The organic layer was then washed with a 1 N aqueoushydrochloric acid solution. The organic layer was then concentrated invacuo with silica gel (2.0 g). The silica gel with absorbed material wasplaced in a SIM and purified via Biotage flash column chromatography (40S silica gel column, 100% ethyl acetate to 10% methanol/ethyl acetate)to afford(S)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(98 mg, 69%) as a white foam: [α]²⁹ _(D)=+12.0°, (c=0.15, methanol);HR-ES(+) m/e calcd for C₂₃H₂₇N₄O₄F₃ [M+H]⁺ 481.2057, observed 481.2055;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (s, 1H), 7.94-8.05 (m, 2H),7.71-7.79 (m, 1H), 7.53 (d, J=2.34 Hz, 1H), 6.40 (d, J=2.13 Hz, 1H),4.99-5.11 (m, 2H), 4.93 (d, J=5.33 Hz, 1H), 4.67-4.76 (m, 2H), 4.09 (dd,J=3.84, 13.85 Hz, 1H), 3.81-3.91 (m, 1H), 3.76 (br. s., 1H), 3.23-3.31(m, 2H), 1.05-2.13 (m, 11H).

Example 6(S)-3-Cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride(5 mL) and N,N-dimethylformamide (5 drops) was treated with a solutionof oxalyl chloride in methylene chloride (2.0 M, 200 μL, 0.40 mmol) andstirred for 15 min at room temperature. After this time, the reactionmixture was then concentrated in vacuo and the resulting residue wasdissolved in methylene chloride (5 mL) and then added dropwise to aseparate reaction flask containing a mixture of(S)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (prepared as in US20080021032, Example 34, 70 mg, 0.45 mmol) and 2,6-lutidine (250 μL) inmethylene chloride (3 mL) at room temperature. The resulting reactionmixture was then stirred at room temperature for 2 h. The reactionmixture was quenched by the addition of methanol and then diluted withmethylene chloride. The organic layer was then washed with a 1 N aqueoushydrochloric acid solution. The organic layer was then concentrated invacuo with silica gel (2.0 g). The silica gel with absorbed material wasplaced in a SIM and purified via Biotage flash column chromatography (40S silica gel column, 100% ethyl acetate to 5% methanol/ethyl acetate) toafford(S)-3-cyclopentyl-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(99 mg, 69%) as a white foam: [α]²⁸ _(D)=−12.0°, (c=0.15, methanol);HR-ES(+) m/e calcd for C₂₃H₂₇N₄O₄F₃ [M+H]⁺ 481.2057, observed 481.2057;¹H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 7.94-8.05 (m, 2H),7.73-7.80 (m, 1H), 7.53 (d, J=2.13 Hz, 1H), 6.40 (d, J=2.13 Hz, 1H),4.98-5.11 (m, 2H), 4.93 (d, J=5.33 Hz, 1H), 4.67-4.75 (m, 2H), 4.09 (dd,J=4.05, 13.64 Hz, 1H), 3.81-3.91 (m, 1H), 3.77 (br. s., 1H), 3.24-3.30(m, 2H), 1.99-2.09 (m, 1H), 1.06-1.95 (m, 10H).

Example 7(S)-3-Cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (50 mg, 0.15 mmol, prepared as in Example 1) in methylene chloride(5 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treatedwith a solution of oxalyl chloride in methylene chloride (2.0 M, 88 μL,0.18 mmol) and stirred at 0° C. for 10 min. After this time, thereaction mixture was warmed to room temperature and then stirred foranother 25 min. After this time, the reaction mixture was thenconcentrated in vacuo and the residue taken up in methylene chloride (2mL) and added dropwise to a separate reaction flask containing a mixtureof 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US20080021032, Example 94, 37 mg, 0.22 mmol) and 2,6-lutidine (32 μL, 0.29mmol) in methylene chloride (5 mL) cooled to 0° C. The resultingreaction mixture was then allowed to warm to room temperature andstirred for 16 h. After such time, the reaction mixture was quenchedwith a saturated aqueous sodium bicarbonate solution (10 mL) and thenextracted with methylene chloride (3×15 mL). The organic layers werethen washed with a 1N aqueous hydrochloric acid solution (10 mL), driedover magnesium sulfate, filtered to remove the drying agent, and thefiltrate concentrated in vacuo. The crude material was purified viaautomated flash chromatography (4 g silica gel column, 50% ethylacetate/hexanes) to afford(S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(51 mg, 71%) as a white foam: [α]³² _(D)=−41.1°, (c=0.09, methylenechloride); HR-ES(+) m/e calcd for C₂₅H₃₁N₄O₃F₃ [M+H]⁺ 493.2421, observed493.2419; ¹H NMR (300 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.01 (t, J=8.60Hz, 2H), 7.68-7.81 (m, 1H), 7.49 (d, J=1.81 Hz, 1H), 6.44 (d, J=2.11 Hz,1H), 4.97-5.17 (m, 2H), 4.71 (d, J=18.41 Hz, 1H), 3.92-4.08 (m, 2H),3.06-3.22 (m, 3H), 0.93-2.16 (m, 17H).

Example 8(S)-3-Cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

A mixture of (S)-(+)-α-aminocyclohexanepropionic acid hydrate (5.00 g,29.2 mmol) and phthalic dicarboxaldehyde (4.21 g, 31.3 mmol) inacetonitrile (120 mL) was refluxed for 20 h under nitrogen. The mixturewas allowed to cool to room temperature and further cooled to 0° C. Thesolid was filtered off and washed once with cold acetonitrile (50 mL) toafford (6.54 g, 78%)(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as awhite solid: EI-HRMS m/e calcd for C₁₇H₂₁NO₃ (M⁺) 287.1521. found287.1521.

To a solution of(S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (60mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared asin US 20080021032, Example 72, 0.031 g, 0.22 mmol) andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride(3 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) dropwiseand the resulting solution stirred at room temperature over night. Thesolution was diluted with methylene chloride, washed with a 1 Nhydrochloric acid solution (15 mL), a saturated sodium chloride solution(20 mL) dried over magnesium sulfate. The mixture was filtered andevaporated and the resulting material purified via automated flashchromatography (Analogix, SF4-40 g column, 70-100% ethylacetate/hexanes) to give(S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide(31 mg, 36%) as an off white solid: [α]²⁸ _(D)=−69.7°, (c=0.31,chloroform); HR-ES(+) m/e calcd for C₂₃H₃₀N₄O₃ [M+H]⁺ 411.2391, observed411.2389; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84-1.24 (m, 7H) 1.47-1.99(m, 2H) 3.18 (s, 4H) 3.49-5.29 (m, 8H) 6.36 (s, 1H) 7.31-7.89 (m, 7H)10.83 (s, 1H).

Example 9(S)-3-Cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of benzene-1,2-dicarbaldehyde (1.9 g, 14 mmol) and(S)-2-amino-3-cyclopentyl-propionic acid (2.0 g, 13 mmol) inacetonitrile was heated to reflux for 17 h. The solution was cooled to4° C. for 3 h during which time a precipitate formed. The mixture wasfiltered and the solid washed with cold acetonitrile and dried undervacuum to give(S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid(3.0 g, 86%) as a white solid: LR-ES(+) m/e calcd for C₁₆H₁₉NO₃ [M+H]⁺274.15, observed 274.1; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.89-2.29 (m,11H), 4.23-5.12 (m, 3H), 7.20-7.99 (m, 4H), 13.00 (s, 1H).

To a solution of(S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid(100 mg, 0.37 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine(prepared as in US 20080021032, Example 72, 0.054 g, 0.38 mmol) andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (Chemimpex, 0.19 g, 0.44 mmol) in methylene chloride(5 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) dropwiseand the resulting solution stirred at room temperature over night. Thesolution was diluted with methylene chloride, washed with a 1 Nhydrochloric acid solution (15 mL), a saturated sodium chloride solution(20 mL) dried over magnesium sulfate. The mixture was filtered andevaporated and the resulting material purified via automated flashchromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes)to give(S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide(94 mg, 65%) as an off white solid: [α]²⁹ _(D)=−62.6°, (C=0.31,chloroform); HR-ES(+) m/e calcd for C₂₂H₂₈N₄O₃ [M+Na]⁺ 419.2053,observed 419.2055; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.01-2.09 (m, 7H),3.18 (s, 4H), 3.61 (t, J=5.28 Hz, 2H), 4.12 (t, J=5.13 Hz, 2H),4.38-5.23 (m, 4H), 6.37 (d, J=2.11 Hz, 1H), 7.32-7.84 (m, 7H), 10.84 (s,1H).

Example 10(S)-3-Cyclopropyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of benzene-1,2-dicarbaldehyde (340 mg, 2.55 mmol) and(S)-2-amino-3-cyclopropyl-propionic acid (300 mg, 2.32 mmol) inacetonitrile (15 mL) was heated to reflux for 18 h. The solution wascooled, concentrated and the residue redissolved in methylene chloride(50 mL). The solution was extracted with a saturated sodium bicarbonatesolution. The layers were separated and the aqueous phase was acidified(pH=2) with hydrochloric acid (3N), extracted with methylene chloride(2×50 mL). The organic phases were combined, dried over magnesiumsulfate, filtered and evaporated to give(S)-3-cyclopropyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic (170 mg,30%) as a yellow solid: LR-ES(+) m/e calcd for C₁₄H₁₅NO₃ [M+H]⁺ 246.29,observed 246.2; ¹H NMR (DMSO-d₆) δ: 7.24-7.94 (m, 4H), 4.83 (dd, J=10.6,4.8 Hz, 1H), 4.54 (s, 2H), 3.16 (d, J=3.6 Hz, 1H), 1.90-2.16 (m, 1H),1.54-1.79 (m, 1H), 0.65 (dd, J=7.8, 5.4 Hz, 1H), 0.29-0.48 (m, 2H),−0.01-0.19 (m, 2H).

To a solution of(S)-3-cyclopropyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (85mg, 0.35 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine(prepared as in US 20080021032, Example 94, 64 mg, 0.38 mmol) andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (Chemimpex, 0.18 g, 0.42 mmol) in methylene chloride(8 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) dropwiseand the resulting solution stirred at room temperature for 4 h. Thesolution was diluted with methylene chloride, washed with a 1 Nhydrochloric acid solution (25 mL), a saturated sodium bicarbonatesolution (25 mL) dried over magnesium sulfate. The mixture was filteredand evaporated and the resulting material purified via automated flashchromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes)to give(S)-3-cyclopropyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide(46 mg, 34%) as an off white solid: [α]³⁰ _(D)=−38.1°, (c=0.21,chloroform); HR-ES(+) m/e calcd for C₂₂H₂₈N₄O₃ [M+H]⁺ 397.2234, observed397.2235; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.03-1.69 (m, 9H), 2.00-2.28(m, 1H), 3.15 (s, 4H), 3.99 (s, 2H), 4.36-5.39 (m, 4H), 6.42 (d, J=1.81Hz, 1H), 7.25-7.88 (m, 6H), 10.80 (s, 1H).

Example 11(S)-3-Cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

To a solution of(S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid(prepared as in Example 9, 94 mg, 0.35 mmol) and1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US20080021032, Example 101, 70 mg, 0.41 mmol) andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (Chemimpex, 0.18 g, 0.41 mmol) in methylene chloride(5 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) dropwiseand the resulting solution stirred at room temperature for 4 h. Thesolution was diluted with methylene chloride, washed with a 1 Nhydrochloric acid solution (25 mL), a saturated sodium bicarbonatesolution (25 mL) dried over magnesium sulfate. The mixture was filteredand evaporated and the resulting material purified via automated flashchromatography (Analogix, SF4-12 g column, 50% ethyl acetate/hexane) toafford(S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide(110 mg, 75%) as an off white solid: [α]³¹ _(D)=−50.6°, (c=0.36,chloroform); HR-ES(+) m/e calcd for C₂₄H₃₂N₄O₃ [M+H]⁺ 425.2547, observed425.2547; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.77-2.18 (m, 17H), 3.40-5.25(m, 8H), 6.39 (d, J=2.11 Hz, 1H), 7.26-7.91 (m, 5H), 10.86 (s, 1H).

Example 12(S)-3-Cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

To a solution of(S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid(prepared as in Example 9, 80 mg, 0.29 mmol) and3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared as in US 20080021032,Example 23, 49 mg, 0.35 mmol) andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (Chemimpex, 0.15 g, 0.35 mmol) in methylene chloride(8 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) dropwiseand the resulting solution stirred at room temperature for 4 h. Thesolution was diluted with methylene chloride, washed with a 1 Nhydrochloric acid solution (25 mL), a saturated sodium bicarbonatesolution (25 mL) dried over magnesium sulfate. The mixture was filteredand evaporated and the resulting material purified via automated flashchromatography (Analogix, SF4-12 g column, 50-70% ethyl acetate/hexanes)to afford(S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide(28 mg, 24%) as an off white solid: HR-ES(+) m/e calcd for C₂₂H₂₈N₄O₃[M+H]⁺ 397.2234, observed 397.2233; ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.94-2.34 (m, 7H), 4.04 (t, J=6.79 Hz, 3H), 4.37-5.28 (m, 6H), 6.39 (s,2H), 7.31-7.90 (m, 8H), 10.86 (s, 2H).

Example 13(S)-3-Cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

To a solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (prepared as in Example 1, 71 mg, 0.21 mmol) and1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032,Example 72, 32 mg, 0.23 mmol) andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride(5 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.62 mmol) dropwiseand the resulting solution stirred at room temperature over night. Thesolution was diluted with methylene chloride, washed with a 1 Nhydrochloric acid solution (15 mL), a saturated sodium bicarbonatesolution (20 mL) dried over magnesium sulfate. The mixture was filteredand evaporated and the resulting material purified via automated flashchromatography (Analogix, SF4-12 g column, 50-80% ethyl acetate/hexanes)to give(S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(42 mg, 43%) as an off white solid: HR-ES(+) m/e calcd for C₂₃H₂₇N₄O₃F₃[M+H]⁺ 465.2108, observed 465.2107; ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.04-2.18 (m, 10H), 3.20 (s, 3H), 3.51-4.28 (m, 4H), 4.60-5.34 (m, 3H),6.40 (d, J=1.81 Hz, 1H), 7.41-8.28 (m, 5H), 10.93 (s, 1H).

Example 14(S)-3-Cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

To a solution of(S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid(prepared as in Example 9, 0.1 g, 0.37 mmol) and1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US20080021032, Example 94, 0.065 g, 0.38 mmol) andbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.19 g, 0.44 mmol) in methylene chloride (10 mL)was added N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) and theresulting solution stirred at room temperature for 19 h. The solutionwas diluted with methylene chloride, washed with a 1 N hydrochloric acidsolution (15 mL), a saturated sodium chloride solution, and dried overmagnesium sulfate. The mixture was filtered and evaporated and theresulting material purified via automated flash chromatography(Analogix, SF15-40 g column, 50%-70% ethyl acetate/hexanes) to afford(S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide(0.063 g, 0.21 mmol, 41%) as an off white solid; [α]²⁹ _(D)=−47.5°(c=0.28, chloroform); HR-ES(+) m/e calcd for C₂₄H₃₂N₄O₃ [M+Na]⁺447.2366, observed 447.2368; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.88 (s,1H), 7.70 (d, J=7.2 Hz, 1H), 7.62 (m, 2H), 7.48 (d, J=2.3 Hz, 1H),7.45-7.54 (m, 1H), 6.43 (d, J=2.3 Hz, 1H), 5.05 (dd, J=10.7, 5.0 Hz,1H), 4.87 (d, J=17.8 Hz, 1H), 4.53 (d, J=17.8 Hz, 1H), 3.99 (s, 2H),3.15 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 0.98-2.10 (m, 11H).

Example 15(S)-3-Cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (prepared as in Example 1, 160 mg, 0.47 mmol) in methylene chloride(10 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treatedwith a solution of oxalyl chloride in methylene chloride (2.0 M, 281 μL,0.56 mmol) and stirred at 0° C. for 15 min. After this time, thereaction mixture was warmed to room temperature and then stirred foranother 30 min. After this time, the reaction mixture was thenconcentrated in vacuo to ˜1 mL volume and an additional amount ofmethylene chloride (3 mL) was added. One half of this solution ofprepared acid chloride (2 mL, 0.23 mmol) was added dropwise to aseparate reaction flask containing a mixture of pyrazin-2-ylamine (33mg, 0.35 mmol) and 2,6-lutidine (52 μL, 0.47 mmol) in methylene chloride(5 mL) cooled to 0° C. The resulting reaction mixture was then allowedto warm to room temperature and stirred for 16 h. After such time, thereaction mixture was quenched with a saturated aqueous sodiumbicarbonate solution (10 mL) and then extracted with methylene chloride(3×10 mL). The organic layers were then washed with a 1N aqueoushydrochloric acid solution (10 mL), dried over magnesium sulfate,filtered to remove the drying agent, and the filtrate concentrated invacuo. The crude material was purified via automated flashchromatography (12 g silica gel column, 25-75% ethyl acetate/hexanes andthen a 4 g silica gel column, 40-60% ethyl acetate/hexanes) to afford(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide(39 mg, 40%) as a white foam: [α]²⁸ _(D)=−65.0° (c=0.10, methylenechloride); HR-ES(+) m/e calcd for C₂₁H₂₁N₄O₂F₃ [M+H]⁺ 419.1690, observed416.1688; ¹H NMR (300 MHz, DMSO-d6) δ ppm 11.32 (s, 1H), 9.26 (s, 1H),8.34-8.49 (m, 2H), 8.02 (t, J=8.45 Hz, 2H), 7.67-7.84 (m, 1H), 5.23 (dd,J=4.98, 10.41 Hz, 1H), 5.06 (d, J=18.41 Hz, 1H), 4.67-4.85 (m, 1H),1.02-2.21 (m, 11H).

Example 16(S)—N-(5-Bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (prepared as in Example 1, 100 mg, 0.29 mmol) in methylene chloride(4 mL) and N,N-dimethylformamide (4 drops) was treated with a solutionof oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) andstirred for 15 min at room temperature. After this time, the reactionmixture was then concentrated in vacuo and the resulting residue wasdissolved in methylene chloride (4 mL) and then added dropwise to aseparate reaction flask containing a mixture of5-bromo-pyrazin-2-ylamine (76 mg, 0.44 mmol) and 2,6-lutidine (100 μL,0.87 mmol) in methylene chloride (3 mL) at room temperature. Theresulting reaction mixture was the stirred room temperature for 1.5 h.The reaction mixture was quenched by the addition of methanol and thendiluted with methylene chloride and the organic layer was washed with a1N aqueous hydrochloric acid solution. The organic layer was then dried,filtered and the filtrate concentrated in vacuo. The crude material waspurified via Biotage flash column chromatography (40 S silica gelcolumn, 25% ethyl acetate/hexanes) to afford(S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(74 mg, 51%) as a white foam: HR-ES(+) m/e calcd for C₂₁H₂₀N₄O₂F₃Br[M+H]⁺ 497.0795, observed 497.0796; ¹H NMR (400 MHz, DMSO-d6) δ ppm11.50 (s, 1H), 9.09 (d, J=1.07 Hz, 1H), 8.65 (d, J=1.28 Hz, 1H), 8.02(dd, J=7.88, 10.44 Hz, 2H), 7.77 (t, J=7.67 Hz, 1H), 5.22 (dd, J=4.90,10.66 Hz, 1H), 5.04 (d, J=18.33 Hz, 1H), 4.76 (d, J=18.11 Hz, 1H),1.04-2.19 (m, 11H).

Example 17(S)-3-Cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (prepared as in Example 1, 160 mg, 0.47 mmol) in methylene chloride(10 mL) was treated with N,N-dimethylformamide (1 drop) and cooled to 0°C. It was then treated with a solution of oxalyl chloride (2.0 M inmethylene chloride, 281 μL, 0.56 mmol) and stirred for 15 min at 0° C.and then warmed to room temperature and stirred for 30 min. After thistime, the reaction mixture was concentrated in vacuo to about 1 mL andthen methylene chloride was added (3 mL). Half of the resulting volume(˜2 mL, ˜0.235 mmol of the in situ generated acid chloride) was added toa flask containing 1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (preparedas in US20080021032, Example 101, 60 mg, 0.35 mmol) and 2,6-lutidine (52μL, 0.47 mmol) in methylene chloride (5 mL) at 0° C. The reactionmixture was then allowed to warm up to room temperature and stirredovernight for 16 h. After this time, the reaction mixture was quenchedwith an aqueous saturated sodium bicarbonate solution (10 mL) andextracted with methylene chloride (3×10 mL). The organic layers werethen combined and washed with a 1N aqueous hydrochloric acid solution,dried over magnesium sulfate, filtered to remove the drying agent andthe filtrate concentrated in vacuo. The crude material was purifiedusing an Analogix Intelliflash 280 chromatography system (4 g silica gelcolumn, 45-55% ethyl acetate/hexanes) to afford(S)-3-cyclopentyl-N-[1-(2-isopropoy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(89 mg, 77%) as a white foam: HR-ES(+) m/e calcd for C₂₅H₃₁N₄O₃F₃ [M+H]⁺493.2421, observed 493.2422; ¹H NMR (300 MHz, DMSO-d₆) δ 10.93 (s, 1H),7.89-8.19 (m, 2H), 7.68-7.83 (m, 1H), 7.56 (d, J=2.11 Hz, 1H), 6.40 (d,J=2.11 Hz, 1H), 4.91-5.25 (m, 2H), 4.71 (d, J=18.41 Hz, 1H), 4.10 (t,J=5.28 Hz, 2H), 3.57-3.79 (m, 2H), 3.47 (td, J=6.15, 12.15 Hz, 1H),0.89-2.17 (m, 17H).

Example 18(S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide

A solution of 3-fluoro-2-methyl-benzoic acid (Aldrich, 10.2 g, 66.17mmol) in methanol (135 mL) at room temperature was treated with borontrifluoride etherate (15 mL) and was allowed to stir at roomtemperature. The reaction mixture was then concentrated in vacuo toremove the methanol and then diethyl ether (−300 mL) was added. Thesolution was transferred to a separatory funnel and washed with water(200 mL) and a 5% aqueous sodium bicarbonate solution to pH>7.5. Theorganic layer was then dried over magnesium sulfate and concentrated invacuo to afford 3-fluoro-2-methyl-benzoic acid methyl ester (9.74 g,87%) as a light orange colored oil which was used without purification.

A solution of 3-fluoro-2-methyl-benzoic acid methyl ester (3.64 g, 21.67mmol) in carbon tetrachloride (100 mL) was treated withN-bromosuccinimide (3.85 g, 21.63 mmol) and benzoyl peroxide (0.1 g).The reaction mixture was then heated at reflux temperature and after 3 hthe heat was removed and it was stirred at room temperature over theweekend. The reaction was then filtered to remove the solids andconcentrated in vacuo to yield a light yellow oil. The reaction was thenrepeated with the remaining 3-fluoro-2-methyl-benzoic acid methyl ester(6.1 g, 36.3 mmol) in carbon tetrachloride using N-bromosuccinimide (6.5g, 36.5 mmol) and benzoyl peroxide (0.1 g) heating at reflux. Thereaction mixture was then filtered and concentrated in vacuo. The twomaterial from the two reactions was combined and purified by flashcolumn chromatography (silica gel, 10% diethyl ether/hexanes) to afford2-bromomethyl-3-fluoro-benzoic acid methyl ester (14.22 g, 99%) as awhite solid.

A solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl esterhydrochloride (Novabiochem, 500 mg, 2.25 mmol) in acetonitrile (20 mL)was placed in a flask and treated with 2-bromomethyl-3-fluoro-benzoicacid methyl ester (557 mg, 2.25 mmol) and triethylamine (660 μL, 4.74mmol). The reaction mixture was then heated at reflux (82° C.) overnightfor 16 h. After this time, the reaction mixture was diluted with water(5 mL) and concentrated in vacuo to remove the acetonitrile. Theremaining material was then diluted with another portion of water (10mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were then dried over magnesium sulfate, filtered to remove thedrying agent and the filtrate concentrated in vacuo. The crude materialwas purified using an Analogix Intelliflash 280 chromatography system(RS-40 silica gel column, 10-25% ethyl acetate/hexanes) to afford(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionicacid methyl ester (411 mg, 57%) as a clear colorless oil: [α]³⁰_(D)=−17.3° (c=0.30, methylene chloride); HR-ES(+) m/e calcd forC₁₈H₂₂NO₃F [M+H]⁺ 320.1657, observed 320.1656; ¹H NMR (300 MHz, DMSO-d₆)δ 7.54-7.63 (m, 2H), 7.42-7.54 (m, 1H), 4.96 (dd, J=4.53, 11.47 Hz, 1H),4.49-4.65 (m, 2H), 3.63 (s, 3H), 1.48-1.99 (m, 7H), 0.74-1.23 (m, 6H).

A mixture of(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionicacid methyl ester (311 mg, 0.97 mmol) in tetrahydrofuran (6 mL) at roomtemperature was treated with a mixture of lithium hydroxide monohydrate(82 mg, 1.95 mL) in water (6 mL). The reaction mixture was then stirredat room temperature until the reaction was complete by TLC (˜2 h). Afterthis time, the reaction mixture was treated with 1N aqueous hydrochloricacid solution until the pH=2. The reaction mixture was then extractedwith ethyl acetate (3×20 mL). The combined organic layers were thendried over magnesium sulfate, filtered to remove the drying agent andthe filtrate was concentrated in vacuo to afford(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionicacid (230 mg, 78%) as a white solid.

A solution of(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionicacid (230 mg, 0.75 mmol) in methylene chloride (10 mL) was treated withN,N-dimethylformamide (1 drop) and cooled to 0° C. It was then treatedwith a solution of oxalyl chloride (2.0 M in methylene chloride, 452 μL,0.91 mmol) and stirred for 15 min at 0° C. and then warmed to roomtemperature and stirred for 30 min. After this time, the reactionmixture was concentrated in vacuo to about 1 mL and then methylenechloride was added (5 mL). One third of the resulting volume (˜2 mL,˜0.25 mmol of the in situ generated acid chloride) was added to a flaskcontaining 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as inUS20080021032, Example 72, 53 mg, 0.38 mmol) and 2,6-lutidine (55 μL,0.50 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixturewas then allowed to warm up to room temperature and stirred overnightfor 16 h. After this time, the reaction mixture was quenched with anaqueous saturated sodium bicarbonate solution (10 mL) and extracted withmethylene chloride (3×10 mL). The organic layers were then combined andwashed with a 1N aqueous hydrochloric acid solution, dried overmagnesium sulfate, filtered to remove the drying agent and the filtrateconcentrated in vacuo. The crude material was purified using an AnalogixIntelliflash 280 chromatography system (4 g silica gel column, 40-60%ethyl acetate/hexanes) to afford(S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide(70 mg, 65%) as a white foam: [α]²⁸ _(D)-63.0° (c=0.10, methylenechloride); HR-ES(+) m/e calcd for C₂₃H₂₉N₄O₃F [M+H]⁺ 429.2297, observed429.2297; ¹H NMR (300 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.41-7.62 (m, 4H),6.39 (d, J=2.11 Hz, 1H), 5.11 (dd, J=4.68, 10.72 Hz, 1H), 4.91 (d,J=17.81 Hz, 1H), 4.61 (d, J=17.81 Hz, 1H), 4.14 (t, J=4.98 Hz, 2H), 3.63(t, J=4.98 Hz, 2H), 3.20 (s, 3H), 1.46-2.02 (m, 7H), 0.83-1.24 (m, 6H).

Example 193-{3-[(S)-3-Cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionicacid tert-butyl ester

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (prepared as in Example 1, 100 mg, 0.29 mmol,) in methylenechloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with asolution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30mmol) and stirred for 15 min at room temperature. After this time, thereaction mixture was then concentrated in vacuo and the resultingresidue was dissolved in methylene chloride (4 mL) and then addeddropwise to a separate reaction flask containing a mixture of3-(3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (prepared as inUS 20080021032, Example 8, 92 mg, 0.44 mmol) and 2,6-lutidine (100 μL,0.87 mmol) in methylene chloride (3 mL) at room temperature. Theresulting reaction mixture was the stirred room temperature for 2 h. Thereaction mixture was quenched by the addition of methanol and thendiluted with methylene chloride and then washed with a 1 N aqueoushydrochloric acid solution. The organic layer was then dried over sodiumsulfate, filtered and the filtrate was then concentrated in vacuo withsilica gel (2.0 g). The silica gel with absorbed material was placed ina SIM and purified via Biotage flash column chromatography (40 S silicagel column, 25% ethyl acetate/hexanes) to afford3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionicacid tert-butyl ester (145 mg, 94%) as a white foam: HR-ES(+) m/e calcdfor C₂₇H₃₃N₄O₄F₃ [M+H]⁺ 535.2527, observed 535.2526; ¹H NMR (400 MHz,DMSO-d₆) δ 10.91 (s, 1H), 8.01 (dd, J=7.67, 12.79 Hz, 2H), 7.71-7.82 (m,1H), 7.56 (d, J=2.13 Hz, 1H), 6.39 (d, J=2.13 Hz, 1H), 4.96-5.14 (m,2H), 4.71 (d, J=18.33 Hz, 1H), 4.19 (t, J=6.50 Hz, 2H), 2.72 (t, J=6.61Hz, 2H), 0.77-2.09 (m, 20H).

Example 203-[3-[(S)-3-Cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl]-propionicacid

A mixture of3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionicacid tert-butyl ester (prepared as in Example 19, 130 mg, 0.24 mmol) inmethylene chloride (3 mL) at room temperature was treated withtrifluoroacetic acid (1 mL) and stirred for 3 h at room temperature. Thereaction mixture was then diluted with chloroform (3 mL) and washed withan aqueous semi-saturated sodium bicarbonate solution. The organic layerwas then dried over magnesium sulfate, filtered to remove the dryingagent, and the filtrate concentrated in vacuo to afford3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionicacid (66 mg, 58%) as a white semi-solid: HR-ES(+) m/e calcd forC₂₃H₂₅N₄O₄F₃ [M+H]⁺ 479.1901, observed 479.1901; ¹H NMR (400 MHz,DMSO-d₆) δ 10.88 (s, 1H), 8.01 (dd, J=7.67, 15.13 Hz, 2H), 7.75 (t,J=7.56 Hz, 1H), 7.53 (d, J=2.13 Hz, 1H), 6.33 (d, J=2.13 Hz, 1H),4.97-5.11 (m, 2H), 4.70 (d, J=18.11 Hz, 1H), 4.06 (t, J=7.46 Hz, 2H),2.25 (t, J=7.35 Hz, 2H), 1.05-2.09 (m, 11H).

Example 21(S)-3-Cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

A solution of(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionicacid (prepared as in Example 1, 125 mg, 0.37 mmol) in methylene chloride(10 mL) was treated with N,N-dimethylformamide (1 drop) and cooled to 0°C. It was then treated with a solution of oxalyl chloride (2.0 M inmethylene chloride, 220 μL, 0.44 mmol) and stirred for 10 min at 0° C.and then warmed to room temperature and stirred for 30 min. After thistime, the reaction mixture was concentrated in vacuo to about 1 mL andthen it was added to a flask containing5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared asin WO2004052869, Example 54, 107 mg, 0.55 mmol) and 2,6-lutidine (81 μL,0.73 mmol) in methylene chloride (10 mL) at 0° C. The reaction mixturewas then allowed to warm up to room temperature and stirred overnightfor 16 h. After this time, the reaction mixture was quenched with anaqueous saturated sodium bicarbonate solution (10 mL) and extracted withmethylene chloride (3×10 mL). The organic layers were then combined andwashed with a 1N aqueous hydrochloric acid solution (10 mL), dried overmagnesium sulfate, filtered to remove the drying agent and the filtrateconcentrated in vacuo. The crude material was purified using an AnalogixIntelliflash 280 chromatography system (12 g silica gel column, 15-40%ethyl acetate/hexanes) to afford(S)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(78 mg, 41%) as a white foam: [α]²⁷ _(D)=−18.0° (c=0.15, methylenechloride); HR-ES(+) m/e calcd for C₂₆H₂₉N₄O₄F₃ [M+Na]⁺ 541.2033,observed 541.2030; ¹H NMR (300 MHz, DMSO-d₆) δ 11.37 (s, 1H), 9.21 (d,J=1.21 Hz, 1H), 8.48 (d, J=1.21 Hz, 1H), 8.02 (t, J=8.00 Hz, 2H),7.72-7.82 (m, 1H), 5.12-5.29 (m, 2H), 5.05 (d, J=17.81 Hz, 1H), 4.76 (d,J=18.11 Hz, 1H), 4.35 (dd, J=6.64, 8.45 Hz, 1H), 3.93 (dd, J=6.64, 8.45Hz, 1H), 1.04-2.20 (m, 17H).

A mixture of(S)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(74 mg, 0.14 mmol) in tetrahydrofuran (1.5 mL) was treated with a 1Naqueous hydrochloric acid solution (1.5 mL) and stirred at roomtemperature until there was no more starting material as indicated byTLC (overnight, ˜16 h). After this time, the reaction was treated with asaturated aqueous sodium bicarbonate solution and then extracted withethyl acetate (3×20 mL). The organic layers were then combined and driedover magnesium sulfate, filtered to remove the drying agent and thefiltrate concentrated in vacuo. The crude material was purified using anAnalogix Intelliflash 280 chromatography system (4 g silica gel column,100% ethyl acetate) to afford(S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide(49 mg, 72%) as a white foam: [α]²⁸ _(D)=−41.6° (c=0.25, methylenechloride); HR-ES(+) m/e calcd for C₂₃H₂₅N₄O₄F₃ [M+H]⁺ 479.1901, observed479.1899; ¹H NMR (300 MHz, DMSO-d₆) δ 11.27 (s, 1H), 9.16 (s, 1H), 8.45(d, J=0.91 Hz, 1H), 8.02 (t, J=8.45 Hz, 2H), 7.70-7.82 (m, 1H), 5.55(br. s., 1H), 5.22 (dd, J=5.13, 10.26 Hz, 1H), 5.05 (d, J=18.11 Hz, 1H),4.90-4.50 (br. s., 1H), 4.75 (d, J=18.11 Hz, 1H), 4.62 (t, J=5.13 Hz,1H), 3.61-3.72 (m, 1H), 3.49-3.60 (m, 1H), 1.03-2.21 (m, 11H).

Example 22(S)—N-[5-((S)-1,2-Dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide

A mixture of (S)-2-amino-4-methylsulfanyl-butyric acid methyl esterhydrochloride (Aldrich, 199 mg, 1 mmol) and2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (prepared asin Example 1, 297 mg, 1 mmol) in acetonitrile (5 mL) and triethylamine(280 μL, 2 mmol) was placed in a microwave reaction vessel and sealed.The reaction mixture was then placed in a microwave reactor and heatedat 115° C. for 15 min. After this time, the reaction mixture was cooledand concentrated with silica gel (2 g) in vacuo. The silica gel withabsorbed material was placed in a SIM and purified via Biotage flashcolumn chromatography (40 S silica gel column, 25% ethylacetate/hexanes) to afford(S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester (137 mg, 40%) as a colorless viscous oil: HR-ES(+) m/ecalcd for C₁₅H₁₆NO₃SF₃ [M+H]⁺ 348.0876, observed 348.0874; ¹H NMR (400MHz, CHLOROFORM-d) δ 8.07 (d, J=7.46 Hz, 1H), 7.83 (d, J=7.67 Hz, 1H),7.64 (t, J=7.67 Hz, 1H), 5.25 (dd, J=4.69, 10.44 Hz, 1H), 4.79 (d,J=17.47 Hz, 1H), 4.53 (d, J=17.47 Hz, 1H), 3.77 (s, 3H), 2.38-2.62 (m,3H), 2.16-2.31 (m, 1H), 2.13 (s, 3H).

A solution of(S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester (134 mg, 0.39 mmol) in tetrahydrofuran/water (6 mL,1:1) was treated with lithium hydroxide monohydrate (33 mg, 0.78 mmol)at room temperature. The reaction mixture was then stirred at roomtemperature for 2 h. After this time, the reaction mixture wasconcentrated in vacuo to remove the tetrahydrofuran. The resultingmaterial was then diluted with a 1N aqueous hydrochloric acid solutionand then extracted with ethyl acetate. The organic layers were combinedand then dried over magnesium sulfate, filtered to remove the dryingagent, and the filtrate was concentrated in vacuo to afford(S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyricacid (126 mg, 97%) as a white foam: HR-ES(+) m/e calcd for C₁₄H₁₄NO₃SF₃[M+H]⁺ 334.0719, observed 334.0717; ¹H NMR (400 MHz, CHLOROFORM-d) δ8.07 (d, J=7.46 Hz, 1H), 7.83 (d, J=7.67 Hz, 1H), 7.59-7.71 (m, 1H),5.25 (dd, J=4.48, 10.44 Hz, 1H), 4.79 (d, J=17.47 Hz, 1H), 4.56 (d,J=17.47 Hz, 1H), 2.41-2.66 (m, 3H), 2.20-2.35 (m, 1H), 2.13 (s, 3H).

A solution of(S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyricacid (57 mg, 0.17 mmol) in methylene chloride (5 mL) andN,N-dimethylformamide (3 drops) at room temperature was treated with asolution of oxalyl chloride (2.0M in methylene chloride, 210 μL, 0.34mmol) and stirred for 15 min. After this time, the reaction mixture wasconcentrated in vacuo and then diluted with methylene chloride (5 mL)and added to a flask containing a solution of5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared asin WO2004052869, Example 54, 67 mg, 0.34 mmol), 2,6-lutidine (64 μL,0.34 mmol) in methylene chloride (2.5 mL) at room temperature. Thereaction mixture was then stirred at room temperature for a period of 2h. After this time, the reaction mixture was treated with methanol andthen diluted with methylene chloride. The reaction mixture was thentransferred to a separatory funnel and washed with a 1N aqueoushydrochloric acid solution. The organic layer was then dried overmagnesium sulfate, filtered to remove the drying agent and the filtratewas concentrated with silica gel (2 g). The silica gel with absorbedmaterial was placed in a SIM and purified via Biotage flash columnchromatography (40 S silica gel column, 40%-60% ethyl acetate/hexanes)to afford(S)—N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide(28 mg, 32%) as a colorless sticky solid.

A solution of(S)—N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide(26 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was treated with a 1Naqueous hydrochloric acid solution (1 mL) and stirred at roomtemperature overnight. The reaction mixture was then concentrated invacuo to remove the tetrahydrofuran and the remaining material waspartitioned between ethyl acetate and a saturated aqueous sodiumbicarbonate solution. The organic layer was separated and dried overmagnesium sulfate, filtered to remove the drying agent and the filtrateconcentrated in vacuo to afford(S)—N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide(20 mg, 85%) as a pale yellow gum: HR-ES(+) m/e calcd for C₂₀H₂₁N₄O₄SF₃[M+H]⁺ 471.1309, observed 471.1306; ¹H NMR (400 MHz, DMSO-d₆) δ 11.15(s, 1H), 9.16 (s, 1H), 8.44 (d, J=1.28 Hz, 1H), 8.02 (t, J=7.46 Hz, 2H),7.71-7.81 (m, 1H), 5.55 (d, J=4.90 Hz, 1H), 5.18 (dd, J=5.01, 9.48 Hz,1H), 4.93-5.02 (m, 1H), 4.77-4.87 (m, 1H), 4.72 (t, J=5.86 Hz, 1H),4.58-4.66 (m, 1H), 3.61-3.71 (m, 1H), 3.55 (td, J=5.86, 11.29 Hz, 1H),2.48-2.65 (m, 3H), 2.22-2.38 (m, 1H), 2.09 (s, 3H).

Example 23(S)-4-Methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid pyrazin-2-ylamide

A mixture of (S)-2-amino-4-methyl-pentanoic acid methyl esterhydrochloride (Aldrich, 273 mg, 1.5 mmol) and2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (prepared asin Example 1, 445 mg, 1.5 mmol) in acetonitrile (5 mL) and triethylamine(420 μL, 3.0 mmol) was placed in a microwave reaction vessel and sealed.The reaction mixture was then placed in a microwave reactor and heatedat 115° C. for 15 min. After this time, the reaction mixture was cooledand concentrated with silica gel (2 g) in vacuo. The silica gel withabsorbed material was placed in a SIM and purified via Biotage flashcolumn chromatography (40 S silica gel column, 20% ethylacetate/hexanes) to afford(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid methyl ester (275 mg, 56%) as a colorless viscous oil.

A solution of(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid methyl ester (274 mg, 0.83 mmol) in tetrahydrofuran/water (12 mL,1:1) was treated with lithium hydroxide monohydrate (70 mg, 1.66 mmol)at room temperature. The reaction mixture was then stirred at roomtemperature for 2 h. After this time, the reaction mixture wasconcentrated in vacuo to remove the tetrahydrofuran. The resultingmaterial was then diluted with a 1N aqueous hydrochloric acid solution(10 mL) and then extracted with ethyl acetate. The organic layers werecombined and then dried over magnesium sulfate, filtered to remove thedrying agent, and the filtrate was concentrated in vacuo to afford(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid (254 mg, 97%) as a white solid.

A solution of(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid (95 mg, 0.30 mmol) in methylene chloride (5 mL) andN,N-dimethylformamide (5 drops) at room temperature was treated with asolution of oxalyl chloride (2.0M in methylene chloride, 200 μL, 0.36mmol) and stirred for 15 min. After this time, the reaction mixture wasconcentrated in vacuo and then diluted with methylene chloride (5 mL)and added to a flask containing a solution of 2-aminopyrazine (Aldrich,57 mg, 0.60 mmol), 2,6-lutidine (250 μL) in methylene chloride (2.5 mL)at 0° C. The reaction mixture was then stirred at room temperature for aperiod of 30 min. After this time, the reaction mixture was treated withmethanol and then diluted with methylene chloride. The reaction mixturewas then transferred to a reparatory funnel and washed with a 1N aqueoushydrochloric acid solution. The organic layer was then dried overmagnesium sulfate, filtered to remove the drying agent and the filtratewas concentrated with silica gel (2 g). The silica gel with absorbedmaterial was placed in a SIM and purified via Biotage flash columnchromatography (40 S silica gel column, 25%-40% ethyl acetate/hexanes)to afford(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid pyrazin-2-ylamide (14 mg, 12%): HR-ES(+) m/e calcd for C₁₉H₁₉N₄O₂F₃[M+H]⁺ 393.1533, observed 393.1532; ¹H NMR (400 MHz, CHLOROFORM-d) δ9.49 (s, 1H), 9.03 (br. s., 1H), 8.29-8.38 (m, 2H), 8.10 (d, J=7.67 Hz,1H), 7.84 (d, J=7.88 Hz, 1H), 7.65 (t, J=7.67 Hz, 1H), 5.14 (dd, J=6.93,8.84 Hz, 1H), 4.69-4.82 (m, 1H), 4.58-4.67 (m, 1H), 1.88-2.15 (m, 2H),1.62 (td, J=6.87, 13.96 Hz, 1H), 1.01-1.10 (m, 6H).

Example 24(S)-4-Methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide

A solution of(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid (prepared as in Example 23, 79 mg, 0.25 mmol) in methylene chloride(5 mL) and N,N-dimethylformamide (5 drops) at room temperature wastreated with a solution of oxalyl chloride (2.0M in methylene chloride,150 μL, 0.30 mmol) and stirred for 15 min. After this time, the reactionmixture was concentrated in vacuo and then diluted with methylenechloride (5 mL) and added to a flask containing a solution of5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared asin WO2004052869, Example 54, 98 mg, 0.50 mmol), 2,6-lutidine (100 μL,0.50 mmol) in methylene chloride (2.5 mL) at room temperature. Thereaction mixture was then stirred at room temperature for a period of 2h. After this time, the reaction mixture was treated with methanol andthen diluted with methylene chloride. The reaction mixture was thentransferred to a separatory funnel and washed with a 1N aqueoushydrochloric acid solution. The organic layer was then dried overmagnesium sulfate, filtered to remove the drying agent and the filtratewas concentrated with silica gel (2 g). The silica gel with absorbedmaterial was placed in a SIM and purified via Biotage flash columnchromatography (40 S silica gel column, 40% ethyl acetate/hexanes) toafford(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (54mg, 44%) as a colorless sticky solid: HR-ES(+) m/e calcd forC₂₄H₂₇N₄O₄F₃ [M+H]⁺ 493.2057, observed 493.2059; ¹H NMR (400 MHz,CHLOROFORM-d) δ 9.37 (d, J=1.28 Hz, 1H), 8.83 (s, 1H), 8.44 (s, 1H),8.08 (d, J=7.46 Hz, 1H), 7.82 (d, J=7.67 Hz, 1H), 7.64 (t, J=7.78 Hz,1H), 5.20 (t, J=6.50 Hz, 1H), 5.13 (dd, J=6.93, 8.84 Hz, 1H), 4.68-4.78(m, 1H), 4.55-4.65 (m, 1H), 4.42 (dd, J=6.82, 8.52 Hz, 1H), 3.95 (dd,J=6.29, 8.42 Hz, 1H), 2.00-2.13 (m, 1H), 1.88-2.00 (m, 1H), 1.53-1.69(m, 1H), 1.44-1.52 (m, 6H), 0.97-1.07 (m, 6H).

A solution of afford(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (53mg, 0.11 mmol) in tetrahydrofuran (1 mL) was treated with a 1N aqueoushydrochloric acid solution (1 mL) and stirred at room temperatureovernight. The reaction mixture was then concentrated in vacuo to removethe tetrahydrofuran and the remaining material was partitioned betweenethyl acetate and a saturated aqueous sodium bicarbonate solution. Theorganic layer was separated and dried over magnesium sulfate, filteredto remove the drying agent and the filtrate concentrated in vacuo toafford(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide (43 mg, 88%) as acream colored foam: [α]²⁹ _(D)=+22.9° (c=0.14, methanol); HR-ES(+) m/ecalcd for C₂₁H₂₃N₄O₄F₃ [M+H]⁺ 453.1744, observed 453.1744; ¹H NMR (400MHz, DMSO-d₆) δ 11.26 (s, 1H), 9.16 (s, 1H), 8.45 (d, J=1.07 Hz, 1H),8.02 (dd, J=7.67, 11.29 Hz, 2H), 7.67-7.85 (m, 1H), 5.55 (d, J=4.90 Hz,1H), 5.28 (dd, J=5.11, 10.65 Hz, 1H), 5.05 (d, J=18.33 Hz, 1H),4.66-4.78 (m, 2H), 4.62 (q, J=4.90 Hz, 1H), 3.67 (td, J=5.30, 10.92 Hz,1H), 3.55 (td, J=5.78, 11.24 Hz, 1H), 1.95-2.09 (m, 1H), 1.71-1.88 (m,1H), 1.49 (br. s., 1H), 0.90-1.00 (m, 6H).

Example 25 In Vitro Glucokinase Activity

The compounds of formula I, which include the compounds set forth in theExamples, were found to activate glucokinase in vitro by the procedureof this Example. In this manner, they increase the flux of glucosemetabolism which causes increased insulin secretion. Therefore, thecompounds of formula I are glucokinase activators useful for increasinginsulin secretion.

Glucokinase In Vitro Assay Protocol:

Glucokinase (GK) was assayed by coupling the production ofglucose-6-phosphate to the generation of NADH with glucose-6-phosphatedehydrogenase (G6PDH, 0.75-1 kunits/mg; Boehringer Mannheim,Indianapolis, Ind.) from Leuconostoc mesenteroides as the couplingenzyme (Scheme 2).

Recombinant human liver GK1 was expressed in E. coli as a glutathioneS-transferase fusion protein (GST-GK) and was purified by chromatographyover a glutathione-Sepharose 4B affinity column using the procedureprovided by the manufacturer (Amersham Pharmacia Biotech, Piscataway,N.J.). Previous studies have demonstrated that the enzymatic propertiesof native GK and GST-GK are essentially identical.

The assay was conducted at 30° C. in a flat bottom 96-well tissueculture plate from Costar (Cambridge, Mass.) with a final incubationvolume of 120 μL. The incubation reaction contained the following: 25 mMHepes buffer (pH 7.1), 25 mM KCl, 5 mM D-glucose, 1 mM ATP, 1.8 mM NAD,2 mM MgCl₂, 1 μM sorbitol-6-phosphate, 1 mM dithiothreitol, test drug or10% dimethylsulfoxide, ˜7 units/ml G6PDH, and GK (see below). Allorganic reagents were >98% pure and were from Boehringer Mannheim withthe exceptions of D-glucose and Hepes which were from Sigma Chemical Co,St Louis, Mo. Test compounds were dissolved in dimethylsulfoxide andwere added to the incubation reaction minus GST-GK in a volume of 12 μLto yield a final dimethylsulfoxide concentration of 10%. This mix waspre-incubated in the temperature controlled chamber of a SPECTRAmax 250microplate spectrophotometer (Molecular Devices Corporation, Sunnyvale,Calif.) for 10 minutes to allow temperature equilibrium and then thereaction was started by the addition of 20 μL GST-GK.

After addition of enzyme, the increase in optical density (OD) at 340 nmwas monitored spectrophotometrically to determine the rate of change(OD₃₄₀ per min). The GK activity (OD₃₄₀/min) in control wells (10%dimethylsulfoxide minus GK activators) was compared with the activity inwells containing test GK activators, and the concentration of activatorthat produced a 50% increase in the activity of GK, i.e., the SC_(1.5),was calculated.

Table 1 below provides the in vitro glucokinase activity for thecompounds in the Examples:

TABLE 1 Example SC1.5 (μM) 1 0.187 2 0.186 3 0.244 4 0.439 5 0.074 60.119 7 0.032 8 3.526 9 1.6 10 20.625 11 2.091 12 1.857 13 0.328 141.242 15 0.176 16 0.062 17 0.179 18 0.962 19 0.334 20 0.457 21 0.255 2214.914 23 1.422 24 2.966

Example 26 In Vivo Glucokinase Activity

Glucokinase Activator In Vivo Screen Protocol in Lean Mice:

Lean C57BL/6J mice were orally dosed via gavage with Glucokinase (GK)activator following a two hour fasting period. Blood glucosedeterminations were made at various (e.g. 0, 1, 2, 4 and 8 hourspost-oral gavage) times during the study.

C57Bl/6J mice were obtained from Jackson Laboratory (Bar Harbor, Me.)and were maintained in a light-dark cycle with lights on from 0600-1800hr. For studies in lean mice, the mice were received at age ten weeksand given ad libitum access to control diet (LabDiet 5001 chow, PMINutrition, Brentwood, Mo.), and were at least age 11 weeks at the timeof study. For studies in the DIO model, the mice were received at agefive weeks and given ad libitum access to Bio-Sery F3282 High Fat Diet(Frenchtown, N.J.), and were at least age 16 weeks at the time of study.The experiments were conducted during the light phase of the light-darkcycle. Mice (n=6) are weighed and fasted for a two hour period prior tooral treatment. GK activators are formulated in Gelucire vehicle(Ethanol:Gelucire44/14:PEG400q.s. 4:66:30 v/w/v). For studies in leanmice, the mice were dosed orally with 5.0 μL per gram of body weight(i.e. 5 ml/kg×10.0 mg/ml formulation to equal a 50 mg/kg dose). Forstudies in DIO mice, the mice were dosed orally with 5.0 μL per gram ofbody weight (i.e. 5.0 ml/kg×5 mg/ml formulation to equal a 25 mg/kgdose). Immediately prior to dosing, a pre-dose (time zero) blood glucosereading was acquired by snipping off a small portion of the animal'stail and collecting 15 μL blood into a heparinized capillary tube foranalysis. Following GK activator administration, additional bloodglucose readings were taken at various time points post dose from thesame tail wound. Results were interpreted by comparing the mean bloodglucose values of vehicle treated mice with GK activator treated miceover the study period. Preferred compounds were considered to be thosethat exhibited a statistically significant (p≦0.05) decrease in bloodglucose compared to vehicle for two consecutive assay time points.

Table 2 below provides data for % glucose lowering of a representativenumber of compounds of the present invention vs. control at 2 hours post25 or 50 mg/kg dose in C57B6 mice:

TABLE 2 Example % gluc lowering @ 2 H Dose (mg/K) 1 −39.8 25 2 −38.8 255 −50.1 25 6 −48.3 25 7 −48.2 25 13 −45.2 50 15 −22.5 25 17 −40.2 25 18−25.4 25 21 −36.6 25

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

What is claimed is:
 1. A compound according to formula (I),

wherein: R₁ is CF₃; R₂ is selected from the group consisting of:isopropyl, cyclopentyl, and —CH₂—S—CH₃; R₃ is

R₄ is selected from the group consisting of: H, Br, and —CH(OH)—CH₂OH ora pharmaceutically-active salt of said compound.
 2. A compound accordingto claim 1, selected from the group consisting of:(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide;(S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;(S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;(S)—N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide;(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid pyrazin-2-ylamide;(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide; andpharmaceutically-acceptable salts thereof.
 3. A compound according toclaim 2, selected from the group consisting of:(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide;(S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;and pharmaceutically-acceptable salts thereof.
 4. A compound accordingto claim 2, selected from the group consisting of:(S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;(S)—N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide;(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid pyrazin-2-ylamide;(S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoicacid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide; andpharmaceutically-acceptable salts thereof.
 5. A compound according toclaim 1, wherein R₂ is cyclopentyl.
 6. A compound according to claim 5,selected from the group consisting of:(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide;(S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;(S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide;and pharmaceutically-acceptable salts thereof.
 7. A pharmaceuticalcomposition, comprising a compound according claim 1 and apharmaceutically-acceptable carrier.